One embodiment of the present invention relates to quinolyl-propylpiperidine derivatives of general formula (I): 
which are active as antimicrobials. Other embodiments of the invention relate to their preparation and to compositions containing them.
Patent Application Publications WO 99/37635 and WO 00/43383 describe antimicrobial quinolylpropylpiperidine derivatives of general formulas: 
In which the radical R1 may be (C1-6)alkoxy; R2 is hydrogen; R3 is at the 2- or 3-position and represents (C1-6)alkyl, which may be optionally substituted with 1 to 3 substituents chosen from thiol, halogen, alkylthio, trifluoromethyl, carboxyl, alkyloxycarbonyl, alkylcarbonyl, alkenyloxycarbonyl, alkenylcarbonyl, hydroxyl optionally substituted with alkyl, and the like; R4 is a group xe2x80x94CH2xe2x80x94R5, wherein R5 is selected from alkyl, hydroxyalkyl, alkenyl, alkynyl, tetrahydrofuryl, phenylalkyl, which is optionally substituted, phenylalkenyl, which is optionally substituted, heteroarylalkyl, which is optionally substituted, heteroaryl, which is optionally substituted, and the like; n is 0 to 2; m is 1 or 2; A and B may be oxygen, sulfur, sulfinyl, sulfonyl, NR11, CR6R7, wherein R6 and R7 represent H, thiol, alkylthio, halo, trifluoromethyl, alkenyl, alkenylcarbonyl, hydroxyl, or amino; and Z1 to Z5 are N or CR1a, and the like.
European Patent Application EP30044, describes quinoline derivatives that are useful as cardiovascular agents and that correspond to the general formula: 
in which R1 may be alkyloxy; Axe2x80x94B is xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CHOHxe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CHOHxe2x80x94, xe2x80x94CH2xe2x80x94COxe2x80x94or xe2x80x94COxe2x80x94CH2xe2x80x94; R1 is H, OH, or alkyloxy; R2 is ethyl or vinyl; R3 may be alkyl, hydroxyalkyl, cycloalkyl, hydroxyl, alkenyl, alkynyl, tetrahydrofuryl, phenylalkyl, diphenylalkyl, which is optionally substituted, phenylalkenyl, which is optionally substituted, benzoyl, or benzoylalkyl, which is optionally substituted, heteroaryl or heteroaryl-alkyl, which is optionally substituted; and Z is H or alkyl or forms with R3 a cycloalkyl radical.
The inventors have now found that the compounds of formula (I) are potent antibacterial agents. In the compounds of formula (I),
R1 represents a, hydrogen atom, a halogen atom, or a hydroxyl, amino, alkylamino, dialkylamino, hydroxyamino, alkyloxyamino, or alkylalkyloxyamino radical;
R2 represents a carboxyl, carboxymethyl, or hydroxymethyl radical;
R3 represents an alkyl radical containing 1 to 6 carbon atoms, substituted with a phenylthio radical, which may itself carry 1 to 4 substituents chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoro-methoxy, carboxyl, alkyloxycarbonyl, cyano, and amino, or substituted with a cycloalkylthio radical in which the cyclic portion contains 3 to 7 members, or substituted with a 5- to 6-membered aromatic heterocyclylthio radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen, and sulfur, and itself optionally substituted with halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoro-methoxy, oxo, carboxyl, alkyloxycarbonyl, cyano, or amino; or
R3 represents a propargyl radical substituted with a phenyl radical, which may itself be substituted with 1 to 4 substituents chosen from halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, carboxyl, alkyloxycarbonyl, cyano, and amino, or substituted with a 3- to 7-membered cycloalkyl radical or substituted with a 5- to 6-membered aromatic heterocyclyl radical comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur, and itself optionally substituted with halogen, hydroxyl, alkyl, alkyloxy, trifluoromethyl, trifluoromethoxy, oxo, carboxyl, alkyloxycarbonyl, cyano, or amino; and
R4 represents an alkyl radical (containing 1 to 6 carbon atoms), alkenyl-CH2xe2x80x94, alkynyl-CH2xe2x80x94 (in which the alkenyl or alkynyl portions contain 2 to 6 carbon atoms), cycloalkyl or cycloalkylalkyl radical (in which the cycloalkyl portion contains 3 to 8 carbon atoms).
The compounds of the invention include the diastereoisomeric forms of the compounds of formula (I), their mixtures, and their cis or trans forms, as well as their salts.
It is understood that the alkyl radicals and alkyl portions of the compounds of the invention may be in the form of a straight or branched chain and contain, unless otherwise stated, 1 to 4 carbon atoms, and that in the alternative case where R1 represents a halogen atom or when R3 carries a halogen substituent, the latter may be chosen from fluorine, chlorine, bromine, and iodine.
Other than in the working examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term xe2x80x9cabout.xe2x80x9d Accordingly, unless indicated to the contrary, the numerical parameters set forth in the following specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.
Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the working examples are reported as precisely as possible. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
In formula (I), when R3 carries an aromatic heterocyclyl substituent, the latter may be chosen, without limitation, from thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrazinyl, and pyrimidinyl.
According to the invention, the compounds of formula (I) may be obtained by condensing an R3 radical with a quinolylpropylpiperidine derivative of formula (II): 
in which R4 is as defined above for compounds of formula (I), Rxe2x80x21 represents a hydrogen atom or a hydroxyl radical, and Rxe2x80x22 represents a protected carboxyl or carboxymethyl radical, to obtain a quinolylpropylpiperidine derivative of formula (III): 
for which Rxe2x80x21, Rxe2x80x22, R3, and R4 are as defined above.
Where appropriate, this reaction may be followed by either a) the halogenation of a derivative for which Rxe2x80x21 is a hydroxyl radical, if it is desired to obtain a quinolylpropylpiperidine derivative for which R1 is a halogen atom, or b) the conversion of a hydroxyl radical to an oxo radical, and then to a hydroxyimino or alkyloxyimino radical according to known methods which do not adversely affect the rest of the molecule, to obtain a quinolylpropylpiperidine derivative of formula (IV): 
for which Rxe2x80x22, R3, and R4 are as defined above, and R5 is a hydrogen atom or an alkyl radical. Where appropriate or desired, this reaction may be followed by: a) the reduction of a derivative of formula (IV) for which R5 is a hydrogen atom to an amine, and optionally by the conversion to a monoalkylated or dialkylated amine; b) the reduction of the derivative of formula (IV) for which R5 is a hydrogen atom to a hydroxylamine; c) the reduction of a derivative of formula (IV) for which R5 is an alkyl radical to an alkyloxyamine, and then, where appropriate to obtain a derivative for which R1 is alkylalkyloxy-amino, the derivative obtained for which R1 is alkyl-oxyamino can be converted by alkylation, and/or d) the reduction of a protected carboxyl radical Rxe2x80x22 to a hydroxymethyl radical according to known methods that do not adversely affect the rest of the molecule. The final step can be optionally followed by the separation of the diastereoisomers, by the separation of the cis and trans forms, by removal, where appropriate, of the acid-protecting radical, and/or by the conversion of the final reaction product obtained to a salt.
The condensation of an R3 radical with piperidine may be carried out by the action of a derivative of formula (V):
R3xe2x80x94Xxe2x80x83xe2x80x83(V)
in which R3 is as defined above and X represents a halogen atom, a methylsulfonyloxy radical, a trifluoro-methylsulfonyloxy radical, or a p-toluenesulfonyloxy radical. The reaction may be carried out, for example, in an anhydrous, inert medium (nitrogen or argon, for example), in an organic solvent such as an amide (dimethylformamide, for example), a ketone (acetone, for example) or a nitrile (acetonitrile, for example) in the presence of a base such as a nitrogen-containing organic base (for example, triethylamine), or an inorganic base (alkali metal carbonate:potassium carbonate, for example) at a temperature ranging from 20xc2x0 C. to the reflux temperature of the solvent.
Examples of derivatives of formula (V) include those for which X is a bromine or an iodine atom.
When R3 represents propargyl substituted with phenyl, cycloalkyl, or heterocyclyl, a propargyl halide may be condensed, and then the chain may be substituted with a phenyl, cycloalkyl, or heterocyclyl radical. In this alternative case, the addition of the propargyl chain may be carried out, for example, by means of propargyl bromide, under the conditions set out above for R3 in the presence or in the absence of an alkali metal iodide such, as for example, potassium or sodium iodide.
When substitution with a phenyl or heterocyclyl radical is involved, the reaction may be carried out by the action of a halide derived from the cyclic radical to be substituted, in the presence of triethylamine, in anhydrous medium, optionally with no solvent or in a solvent such as an amide (dimethyl-formamide, for example) or a nitrite (acetonitrile, for example) and in the presence of a palladium salt such as, for example, tetrakis(triphenylphosphine)palladium and copper(I) iodide, at a temperature ranging from 20xc2x0 C. to the reflux temperature of the solvent.
When substitution with a cycloalkyl group is involved, the reaction may be carried out by the action of an organolithium compound such as n-butyllithium or tert-butyllithium on the propargyl derivative obtained above, in anhydrous medium in an ether such as, for example, tetrahydrofuran at a temperature ranging from xe2x88x9278 to 0xc2x0 C., followed by the action of a cycloalkanone and then by the deoxygenation of the intermediate alcohol according to conventional methods.
It is understood that when the alkyl radicals represented by R3 carry carboxyl or amino substituents, the latter can be protected beforehand and then released after the reaction. The procedure can be carried out according to customary methods which do not adversely affect the rest of the molecule, for example, according to the methods described by T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (2nd ed.), A. Wileyxe2x80x94Interscience Publication (1991), or by Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973), both of which are hereby incorporated herein by reference.
The protected carboxyl or carboxymethyl radical represented by Rxe2x80x22 may be chosen from an easily hydrolyzable ester. These esters include, for example, methyl, benzyl, tert-butyl esters, allyl, or phenylpropyl esters. Optionally, the carboxyl radical may be protected simultaneously with the reaction. In this case, the derivative of formula (II) used carries a radical Rxe2x80x22=carboxyl or carboxymethyl.
The halogenation intended to obtain a quinolylpropylpiperidine derivative for which R1 is a halogen atom, from the derivative for which Rxe2x80x21 is hydroxyl, may be carried out in the presence of an aminosulfur trifluoride (diethylaminosulfur trifluoride, bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor(copyright)), or morpholinosulfur trifluoride, for example) or alternatively in the presence of sulfo tetrafluoride. The fluorination reaction may also be carried out by the action of a fluorinating agent such as a sulfur fluoride [for example, morpholinosulfur trifluoride, sulfur tetrafluoride (J. Org. Chem., 40, 3808 (1975), which is hereby incorporated by reference), diethylaminosulfur trifluoride (Tetrahedron, 44, 2875 (1988)), bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor(copyright)). Alternatively, the fluorination reaction may also be carried out by means of a fluorinating agent such as hexafluoropropyldiethylamine (See JP 2 039 546) or N-(2-chloro-1,1,2-trifluoroethyl)diethylamine. The halogenation reaction may also be carried out using a reagent such as a tetraalkylammonium, trialkylbenzyl-ammonium, or trialkylphenylammonium halide or using an alkali metal halide optionally substituted with a crown ether.
When a tetraalkylammonium halide is used, the latter may be chosen, by way of example, from tetra-methylammonium, tetraethylammonium, tetrapropyl-ammonium, tetrabutylammonium (tetra-n-butylammonium, for example), tetrapentylammonium, tetracyclohexylammonium, triethylmethylammonium, tributylmethylammonium, and trimethylpropylammonium halides.
The procedure may be carried out in an organic solvent such as a chlorinated solvent (for example, dichloromethane, dichloroethane, or chloroform) or in an ether (tetrahydrofuran or dioxane, for example) at a temperature ranging from xe2x88x9278 to 40xc2x0 C., for example, from 0 to 30xc2x0 C.). It is advantageous to carry out the procedure in an inert medium, argon or nitrogen, for example.
It is also possible to carry out the procedure by treatment with a halogenating agent such as thionyl chloride or phosphorus trichloride in an organic solvent such as a chlorinated solvent (dichloromethane or chloroform, for example), at a temperature ranging from 0xc2x0 C. to the reflux temperature of the reaction mixture.
The conversion of the hydroxyl radical to an oxo radical may be carried out using conventional oxidation methods described in the literature, such as in D. Swern oxidation, J. O. C., 44, 41-48 (1979), which is hereby incorporated by reference, for example, in the presence of oxalyl chloride and of dimethyl sulfoxide, optionally in a solvent such as dichloromethane, or without solvent, at a temperature ranging from xe2x88x9260 to 20xc2x0 C., followed by the conversion of the oxo radical to a hydroxyimino or alkyloxyimino radical.
The conversion of the oxo radical to a hydroxyimino or alkyloxyimino radical may be carried out by the action of hydroxylamine (hydroxylamine hydrochloride, for example) or of alkyloxyamine, optionally in hydrochloride form, in a solvent such as pyridine or an alcohol (such as methanol or ethanol, for example) and in the presence of a nitrogen base such as triethylamine or pyridine at a temperature ranging from 0 to 60xc2x0 C.
The reduction of a derivative of formula (IV), for which R5 is hydrogen, to an amine may be carried out according to customary methods that do not adversely affect the rest of the molecule, for instance, by the action of a reducing agent such as, for example, a hydride (alkali metal borohydride, such as sodium or potassium borohydride; or aluminum and lithium hydride) in the presence or in the absence of molybdenum oxide, the procedure may be carried out under an inert atmosphere (nitrogen or argon, for example), in an organic solvent such as an alcohol (methanol, ethanol or isopropanol, for example) or a chlorinated solvent (for example, dichloromethane) at a temperature ranging from xe2x88x9210 to 40xc2x0 C.
The reduction of a derivative of formula (IV) to a hydroxylamine or to an alkyloxyamine may be carried out, for example, in the presence of an organic acid (carboxylic acid such as, for example, acetic acid), by the action of a reducing agent such as, for example, a hydride chosen from sodium triacetoxy-borohydride (optionally prepared in situ) or sodium cyanoborohydride. In one embodiment of the invention, this reaction is carried out under an inert atmosphere (nitrogen or argon, for example), in an organic solvent such as an alcohol (methanol, ethanol or isopropanol, for example) or a chlorinated solvent (for example, dichloromethane) at a temperature ranging from xe2x88x9230 to +40xc2x0 C.
The conversion of the amino radical represented by R1 to an alkylamino or dialkylamino radical may be carried out according to customary methods, for example, by the action of an alkyl halide, optionally in a basic medium in the presence of a nitrogen base such as a trialkylamine (triethylamine, diisopropylethylamine, and the like), pyridine, or in the presence of an alkali metal hydride (sodium hydride), in an inert solvent such as an amide (dimethylformamide, for example) or an oxide (dimethyl sulfoxide, for example), at a temperature ranging from 20xc2x0 C. to the reflux temperature of the reaction medium.
The conversion of the alkyloxyamino radical represented by R1 to an alkylalkyloxyamino radical may be carried out according to the method described above for the alkylation of the amine.
The removal, where appropriate, of the acid-protecting radical to obtain a quinolylpropylpiperdine derivative for which R2 is a carboxyl or carboxymethyl radical may be carried out according to the usual methods, for example, by acid hydrolysis or saponification of the ester Rxe2x80x22. For instance, sodium hydroxide may be caused to act in an aqueous-organic medium, for example in an alcohol such as methanol or an ether such as dioxane, at a temperature ranging from 20xc2x0 C. to the reflux temperature of the reaction mixture. It is also possible to use hydrolysis in aqueous hydrochloric medium at a temperature ranging from 20 to 100xc2x0 C.
Where appropriate, a derivative of formula (I) for which R2 is hydroxymethyl may be prepared from a derivative for which Rxe2x80x22 is protected carboxyl. For example, the procedure may be carried out by reducing the product protected in the form of an ester Rxe2x80x22, according to the customary methods that do not adversely affect the rest of the molecule, for example, by the action of a hydride (aluminum and lithium hydride or diisobutylaluminum hydride, for example) in a solvent such as an ether (tetrahydrofuran, for example) at a temperature ranging from 20 to 60xc2x0 C.
A quinolylpropylpiperidine derivative of formula (II) for which Rxe2x80x22 represents a protected carboxymethyl radical, and Rxe2x80x21 is a hydrogen atom, may be prepared by selective hydrogenation of a quinolylpropylpiperidine derivative of formula (VI): 
in which R4 is as defined above and Rxe2x80x32 is the protected carboxyl radical corresponding to Rxe2x80x22, and in which the amine functional group of the piperidine is protected beforehand, at a pressure between 1 to 100 bar and at a temperature ranging from 20 to 80xc2x0 C., in a solvent such as, for example, an alcohol (ethanol, for example) or an amide (dimethylformamide, for example) in the presence of a catalyst, for example, palladium on carbon or palladium on barium sulfate.
The protection of the amino group of the piperidine may be carried out according to customary methods that do not adversely affect the rest of the molecule and that are compatible with the reaction, for example, according to the references cited above. In one embodiment of the invention, the protective radical is the benzyloxycarbonyl radical. In this case, the hydrogenation reaction leads directly to the deprotection of the amine.
A quinolylpropylpiperidine derivative of formula (VI) may be prepared by condensing a quinoline derivative of formula (VII): 
in which R4 is as defined above and Hal represents an iodine or bromine atom, with a piperidine derivative of formula (VIII): 
in which Rxe2x80x32 is as defined above and Rz represents an amino-protecting radical.
The reaction may be carried out by the successive action of an organoborane (9-borabicyclo[3.3.1]nonane, for example) in a solvent such as an ether (tetrahydrofuran or dioxane, for example) at a temperature ranging from xe2x88x9220 to 20xc2x0 C., followed by the addition of a quinoline derivative of formula (VII), by analogy with the methods described by Suzuki et al., Pure and Appl. Chem., 57, 1749 (1985), which is hereby incorporated by reference. The reaction is generally carried out in the presence of a palladium salt (palladiumdiphenylphosphinoferrocene chloride, for example) and of a base such as potassium phosphate, at a temperature ranging from 20xc2x0 C. to the reflux temperature of the solvent.
A piperidine derivative of formula (VIII) may be prepared by the Wittig reaction, by condensing a phosphorus ylide with a piperidine derivative of formula (IX): 
in which Rz is as defined above.
In one embodiment of the invention, the procedure is carried out using methyl (triphenylphosphoranylidene)acetate, in a solvent such as, for example, toluene, at a temperature ranging from 20 to 110xc2x0 C.
The 3-oxopiperidine derivative of formula (IX) may be prepared according to or by analogy with the method described by Y. Takeuchi et al., Synthesis, 10, 1814 (1999), which is hereby incorporated by reference.
The quinolylpropylpiperidine derivative of formula (II), for which Rxe2x80x22 is a carboxyl radical and Rxe2x80x21 is a hydrogen atom, may be prepared from the corresponding derivative for which Rxe2x80x22 is protected carboxymethyl, by reducing this radical to an alcohol, converting to a p-toluenesulfonyloxy derivative, and then converting this derivative to a vinyl derivative by an elimination reaction followed by the oxidation of the derivative obtained.
According to another embodiment of the invention, a quinolylpropylpiperidine derivative of formula (II), for which Rxe2x80x22 is a carboxyl radical and Rxe2x80x21 is a hydrogen atom, may be prepared by condensing a quinoline derivative of formula (VII) as defined above, with a piperidine derivative of formula (X): 
in which Rz is as defined above, and Rxe2x80x22 represents a protected carboxyl radical as defined above, followed by removal of the amino-protecting radical Rz.
The reaction can be carried out under conditions similar to the conditions described for the reaction of the quinoline derivative of formula (VII) and of a piperidine derivative of formula (VIII). The elimination of the radical Rz can be carried out according to the methods cited above, according to the examples, or as described by T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (2nd ed.), A. Wiley-Interscience Publication (1991), or by Mc Omie, Protective Groups in Organic Chemistry, Plenum Press (1973).
A compound of formula (X) may be prepared according to or by analogy with the method described below in the examples.
The reduction, in alcohol, of the acid protected in the form of a radical Rxe2x80x22 at the 3-position of the piperidine, to a hydroxyethyl radical can be carried out according to customary methods that do not adversely affect the rest of the molecule, for example, the procedure can be carried out by the action of a hydride (lithium and aluminum hydride or diisobutylaluminum hydride, for example) in a solvent such as an ether (tetrahydrofuran, for example) at a temperature ranging from 20 to 60xc2x0 C.
The conversion of a quinolylpropyl-piperidine derivative for which Rxe2x80x22 is hydroxyethyl to a p-toluenesulfonyloxyethyl derivative can be carried out, for example, according to the method described by L. F. Fieser and M. Fieser, Reagents for Organic Synthesis, vol. 1, 1179 (1967), which is hereby incorporated by reference, starting with p-toluenesulfonyl chloride in the presence of a base such as a tertiary amine (for example, triethylamine) or an aromatic amine (for example, pyridine), in a halogenated solvent (for example, dichloromethane) or without solvent, at a temperature ranging from 0 to 50xc2x0 C.
The conversion of the p-toluenesulfonyloxy-ethyl derivative to a vinyl derivative can be carried out by an elimination reaction, for example, according to the method described by A. Sharma et al., Org. Prep Proced. Int., 25(3), 330-333 (1993), which is hereby incorporated by reference, in the presence of a base such as, for example, potassium t-butoxide in a solvent such as dimethylsulfoxide, for example, at a temperature ranging from 20 to 100xc2x0 C.
The conversion of a vinyl derivative to a derivative for which Rxe2x80x22 is carboxyl is carried out by the oxidation methods described in the literature, for example, using sodium metaperiodate in the presence of ruthenium trichloride hydrate, in a mixture of solvents such as, for example, the water/acetonitrile mixture, at a temperature ranging from 20 to 60xc2x0 C.
A quinolylpropylpiperidine derivative of formula (II) for which Rxe2x80x21 is a hydroxyl radical may be prepared by oxidizing, in a basic medium, the corresponding derivative for which Rxe2x80x21 is a hydrogen atom. The oxidation is carried out by the action of oxygen, for example, in an inert solvent such as dimethyl sulfoxide, in the presence of tert-butanol and a base such as potassium or sodium tert-butoxide, at a temperature ranging from 0 to 100xc2x0 C.
The quinoline derivatives of formula (VII) for which Hal is an iodine atom may be prepared by analogy with the work by E. Arzel et al., Tetrahedron, 55, 12149-12156 (1999), which is hereby incorporated by reference, from 3-fluoro-6-methoxyquinoline, by the successive action of a base and then of iodine. Lithium diisopropylamide may be used, for example, in a solvent such as an ether (tetrahydro-furan) at a temperature ranging from xe2x88x9280 to 20xc2x0 C. The 3-fluoro-3-methoxyquinoline may be obtained by pyrolysis of 6-methoxyquinoline diazonium 3-tetra-fluoroborate or 3-hexafluorophosphate according to the Balz-Schieman reaction, Org. Synth., Coll 5, 133 (1973), which is hereby incorporated by reference, at a temperature ranging from 100 to 240xc2x0 C. The 6-methoxyquinoline diazonium 3-tetrafluoroborate or 6-methoxyquinoline diazonium 3-hexafluorophosphate may be obtained from 3-amino-6-methoxyquinoline by the action of an alkali metal nitrite (sodium nitrite for example) in an acid medium (tetrafluoroboric acid or hexafluorophosphoric acid) in a solvent such as water, at a temperature ranging from xe2x88x9210 to +20xc2x0 C., by analogy with the work by A. Roe et al., J. Am. Chem. Soc., 71, 1785-86 (1949), which is hereby incorporated by reference or by the action of an alkyl nitrite (such as, for example, isoamyl nitrite) and of the complex of diethyl ether trifluoroborate in a solvent such as an ether (tetrahydrofuran, for example) at a temperature ranging from xe2x88x9210 to +10xc2x0 C. The 3-amino-6-methoxyquinoline can be prepared as described by N. Heindel, J. Med. Chem., 13, 760 (1970), which is hereby incorporated by reference. The quinoline derivative of formula (VII) for which Hal is a bromine atom may also be prepared by analogy with this method.
The intermediates of the quinolylpropyl-piperidine derivatives for which R4 represents alkenyl-CH2xe2x80x94, alkynyl-CH2xe2x80x94, cycloalkyl or cycloalkyl-alkyl may be obtained by analogy with the preparation of the intermediates for which R4 is alkyl, by the action of the corresponding halogenated derivative on the quinoline derivative hydroxylated at the 6-position.
It is understood that the derivatives of formula (I), (II), (III), (IV) and their starting intermediates may exist in the cis or trans form at the level of the substituents at the 3- and 4-position of piperidine. The derivatives of the trans configuration may be obtained from the derivatives of the cis configuration according to or by analogy with the method described in International Application WO 99/37635, which method is hereby incorporated by reference.
The quinolylpropylpiperdine derivatives of formula (I) may be purified, where appropriate, by physical methods such as crystallization or chromatography.
Moreover, it is understood that when R1 is other than a hydrogen atom, diastereoisomeric forms may exist and that the diastereoisomeric forms and mixtures thereof also fall within the scope of the present invention. Diastereoisomeric mixtures may be separated, for example, by chromatography on silica or by High-Performance Liquid Chromatography (HPLC). Likewise, the cis and trans derivatives may be separated by chromatography on silica or by High-Performance Liquid Chromatography (HPLC).
The quinolylpropylpiperidine derivatives of formula (I) may be converted to addition salts with acids by known methods. It is understood that these salts also fall within the scope of the present invention.
Examples of addition salts with pharmaceutically acceptable acids include the salts formed with inorganic acids (for example, hydrochlorides, hydrobromides, sulfates, nitrates, and phosphates) or with organic acids (for example, succinates, fumarates, tartrates, acetates, propionates, maleates, citrates, methanesulfonates, ethanesulfonates, phenyl-sulfonates, p-toluenesulfonates, isethionates, naphthylsulfonates, and camphorsulfonates, or with the substitution derivatives of these compounds).
Some of the quinolylpropylpiperidine derivatives of formula (I) carrying a carboxyl radical may be converted to the form of metal salts or to addition salts with the nitrogen bases according to methods known per se. These salts also fall within the scope of the present invention. The salts may be obtained by the action of a metal base (for example, an alkali or alkaline-earth metal), ammonia or an amine, on a product according to the invention, in an appropriate solvent such as an alcohol, an ether, or water, or by an exchange reaction with a salt of an organic acid. The salt formed precipitates after optional concentration of the solution, it may be separated by filtration, decantation, or freeze-drying. Examples of pharmaceutically acceptable salts include the salts formed with alkali metals (sodium, potassium, lithium) or alkaline-earth metals (magnesium, calcium), the ammonium salt, and the salts of nitrogen bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, N,N-dimethylethanol-amine, benzylamine, dicyclohexylamine, N-benzyl-xcex2-phenethylamine, N,Nxe2x80x2-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, chloline, arginine, lysine, leucine, and dibenzylamine).
The quinolylpropylpiperidine derivatives according to the invention are useful advantageous antibacterial agents.
In vitro, on gram-positive microbes, the quinolylpropylpiperidine derivatives according to the invention have proved active at concentrations ranging from 0.03 to 4 xcexcg/ml on meticillin-resistant Staphylococcus aureus AS5155, also at concentrations ranging from 0.06 to 8 xcexcg/ml on Streptococcus pneumoniae 6254-01 and at concentrations ranging from 0.06 to 64 xcexcg/ml on Enterococcus faecium H983401. On gram-negative microbes they have proved active at concentrations ranging from 0.32 to 32 xcexcg/ml on Moraxella catharrhalis IPA152; in vivo, they have proved active on experimental infections of mice with Straphylococcus aureus IP8203 at doses ranging from 12 to 150 mg/kg by the subcutaneous route (CD50) and for some of them at doses ranging from 26 to 150 mg/kg by the oral route.
Finally, the compounds according to the invention are also useful, because of their low toxicity to the host. None of the compounds exhibited toxicity at the dose of 100 mg/kg by the subcutaneous route in mice (2 administrations).
Examples of the quinolylpropylquinoline derivatives of the invention include:
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluorophenylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(n-propylthio)propyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(n-butylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopropylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclobutylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(5-fluorothien-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-3-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluoropyridin-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3-fluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]-piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl])1-[3-(thien-3-yl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluorophenylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(n-propylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(n-butylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopropylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclobutylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(5-fluorothien-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-3-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3S,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluoropyridin-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3-fluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]-piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluoro-phenyl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]1-[2-(2,3,5-trifluorophenylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(n-propylthio)propyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(n-butylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopropylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclobutylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(5-fluorothien-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-3-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-3-yl)thioethyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3-fluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)-prop-2-ynyl]piperidine-3-carboxylic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluorophenylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(n-propylthio)propyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(n-butylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopropylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclobutylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(5-fluoro-thien-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-3-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluoropyridin-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3-fluorophenyl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluorophenylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(n-propylthio)propyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(n-butylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopropylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclobutylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(5-fluorothien-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-3-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluoropyridin-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3-fluorophenyl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-hydroxy-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,5-difluorophenylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclohexylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluoro-phenyl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-fluoro-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)-prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-(2-phenylthioethyl)piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluorophenylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3,5-difluorophenylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(2,3,5-trifluorophenylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(n-propylthio)propyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S) amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(n-butylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopropylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclobutylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl-1-[2-(cyclohexylthio)ethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(5-fluoro-thien-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(thien-3-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(1,3-thiazol-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(pyridin-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[2-(3-fluoropyridin-2-yl)thioethyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3-fluorophenyl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,5-difluorophenyl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(3,5-difluorophenyl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(2,3,5-trifluorophenyl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-2-yl)prop-2-ynyl]piperidine-3-acetic acid
(3RS,4RS) or (3SR,4RS)-4-[3-(R,S)-amino-3-(3-fluoro-6-methoxyquinolin-4-yl)propyl]-1-[3-(thien-3-yl)prop-2-ynyl]piperidine-3-acetic acid
as well as their salts.
The following examples illustrate the present invention but do not limit it.